Formation of enolate ions and their Michael addition to unsaturated molecules containing electron-withdrawing groups are key reactions for generation of carbon-carbon bonds in a variety of applications (Carruthers et al., Modern Methods of Organic Synthesis, Cambridge University Press (0521778301)). Considering the present interest in “green” processes (Jackson, Adhesives and Sealants Industry, Apr. 2006, 20-25), Michael additions have many attractive attributes when one can avoid solvents and use catalytic amounts of base. These reactions maximize atom economy, are largely made from natural feedstocks (with the current exception of acrylic acid), and are readily degraded by ester hydrolysis in the environment.
Acrylated oligomers with high functional density are useful starting points for making structured Michael addition products. To be most useful, the products from addition to these oligomers must not create formulated viscosities that are too high to be applied by the usual coating means. For example, in the printing industry using flexography, the final ink viscosity must be less that 1 Pa·s. The use of solvents for the purpose of viscosity reduction is limited due to VOC or migration restrictions in packaging applications of such inks. Thus is it preferable to make structures with low intrinsic viscosity and Newtonian flow under shear.
The most common Michael donors are acetoacetyl esters with two acidic CH bonds (a methylene) between the carbonyl groups. To avoid high polymer and gelation in the base-catalyzed addition to polyacrylates at close to stoichiometric 1:1 equivalents ratio, there is a need to control the reaction of these two sites such that only the enolate derived from the methylene reacts with the Michael acceptor to the exclusion of the enolate from the methine formed after the first addition. While this is the order expected by thermodynamics (pKa typically 11 and 13, respectively), the most common result is dialkylation when stoichiometric ratios of donors and acceptor functions are used (approximately one mole of methylene donor to one equivalent of olefin acceptor) under basic conditions (either stoichiometric or catalytic base). Our attempts to vary the basicity of the medium to select between the two acids only resulted in the expected rate change but without any appreciable effect on product selectivity.
It has been proposed that the monomeric enolate ion pairs are the reactive species in addition and substitution reactions (Zaugg, J. Ratajczyk, J. Leonard, and A. Schaefer, J. Org. Chem., 37(14), 2249-2253 (1972)). Aggregation decreases as the degree of substitution increases (Streitwieser, Y. Kim, and D. Wang, Organic Letters, 3(16), 2599-2601 (2001)). Thus while the substituted (methine) enolate is less favored by thermodynamics, the Michael product from it may be more likely to form due to the higher than expected concentration of the corresponding monomeric mono-substituted ion. This proposal is supported in experimental data on lithium enolates in THF solvent (Facchetti et al. J. Org. Chem., 69, 8345-8355 (2004)).
In contrast, it has also been proposed that polyalkylation is favored by aggregation of the enolate (House, M. Gall and H. D. Olmstead, J. Org. Chem. 36, 2361-2371 (1971)). There are many publications that demonstrate that the order of increasing aggregation is R4N+˜K+<Na+<Li+. According to this mechanism, one would not expect enolates with Na+ or Li+ counterions to be especially capable of very high selectivity for monoalkylated products in the catalyzed Michael addition of acetoacetyl esters to polyacrylate acceptors. This statement is supported by the following experimental evidence.
Clemens et al. (61(770), 83-91 (1989)) discloses information concerning the effect of base identity on the ratio of bis- to mono-alkylation in the Michael addition of isobutyl acetoacetate to ethyl acrylate. Here, the selectivity observed is attributed to the nature of the base, e.g., hydroxide versus amidine. No observation of an effect of the enolate counterion is reported.
In a paper by Iwamura et. al. (Tetrahedron Letters, 46, 6275-7 (2005)) on the addition to a monoacrylate of the enolate formed using KOH base from a sterically hindered acetoacetate at 3/2 equivalents ratio, respectively, the result is predominately di-addition even at low temperature.
Bonadies et. al. (Gazetta Chimica Italiana, 124, 467-468 (1994)) reports excellent yields of conjugate addition to methylvinylketone using LiOH catalyst in dimethoxyethane (DME) solvent. But since both ethyl acetoacetate and ethyl 2-ethylacetoacetate give rapid rates of addition under the same conditions, no specific control of Michael polyaddition would seem possible under these conditions.
Ye et al. (Tetrahedron Letters, 46, 6875-8 (2005)) reports that guanidine bases give a high yield of monoaddition with dimethyl malonate and cyclopent-2-en-1-one in toluene solvent.
U.S. Pat. No. 5,667,901 describes products from use of 1:1 equivalents and higher of acetoacetate esters in Michael addition with TMPTA catalyzed by sodium methoxide. Both structures from monoaddition and diaddition are characterized in this document as products of reaction.
In summary, there is a long-standing problem with polyalkylation in Michael addition of methylene enolate anions (donors) to carbonyl-activated olefins (acceptors) that can generate a complex mixture of products. Various means have been proposed to address this problem.
The simplest is the inclusion of protic acid solvents of pKa intermediate between the methylene and methine protons of the unsubstituted and monosubstituted 1,3-dicarbonyls, respectively (e.g., the effect of butyl alcohol in a DBU-catalyzed reaction of ethylacetoacetate in Graham et al. (Water-Borne, High Solids, and Powder Coatings Symposium, Feb. 24-26, 1993). To the extent that this could be successful given only a two pK unit difference in acidity and the large number of competing processes (transesterification, alcohol addition, and reverse Claisen) as can proceed with alcohols, the requirement for volatile solvent limits its application.
Other disclosed procedures use formation of complex organometallics such as from the reaction of an enolsilane with a Lewis acid (reviewed in Reetz et al., Tetrahedron Letters, 34(46), 7395-8 (1993)), formation of an amine-manganese complex (Cahiez et al., Tetrahedron Letters, 35(19), 3065-8 (1994)), or formation of an alkyl zinc compound (Morita, M. Suzuki, R. Noyori, J. Org. Chem., 54, 1787-8 (1989)). However, these also require specialized solvents and conditions or leave objectionable metals in the product unless additional steps are taken.
More effectively, an activating ester group can be introduced by Claisen condensation followed by its removal by decarboxylation after alkylation (Caine, Comprehensive Organic Synthesis, B. Trost and I. Fleming, eds., Vol. 3, p. 1, Pergamon Press, Oxford, 1991). However, there are at least two additional steps that limit construction of an efficient process.
The problem becomes even more acute when it is desired to use poly-unsaturated Michael acceptors (e.g., trimethylolpropane triacrylate, TMPTA) where rapid generation of high molecular weight by branching through extensive dialkylation at stochiometries near 1:1 equivalent ratios can gel reactors. To avoid these gels, large excesses of either donor or acceptor functions can be used to make oligomers (10 to 1000 Pa·s. at 25° C.) in a soluble, strong base-catalyzed process (U.S. Pat. Nos. 5,569,779; 5,536,872; 5,430,177; 5,350,875; 5,347,043; 6,706,414 B1; 6,025,410; WO 01/00684 A1; U.S. Pat. No. 5,945,489). These products by necessity include unreacted starting donor or acceptor molecules that limit the chemist's options in the use of these materials. And if reaction is carried beyond 50% consumption of either component in excess (just short of the gel point as measured in Clemens et al. (61(770), 83-91 (1989)), large amounts of diluent must be added to restore viscosities for such products to be useful as lubricants and coatings.
In a parallel development, monofunctional reactants in admixture with polyfunctional reactants can function as chain terminating groups in these addition polymerizations, limiting the opportunities of extension to higher molecular weight (EP 1 431 320; U.S. Pat. No. 6,897,264; and U.S. Pat. No. 6,855,796). This approach needs at least one equivalent of monofunctional donor or acceptor to block roughly half of the polyfunctional acceptor or donor sites. Use of monofunctional donors or acceptors limits the number of remaining acceptor or donor functions, respectively, that can be used in a subsequent reaction.
The products from either of these above classical approaches to limiting molecular weight are still characterized by a high degree of shear-thinning coming from entanglement of the linear and branched segments present in the fraction of very high molecular weight that remains even in short-stopped products of these processes.
Clearly, based on the above, there is no indication in the prior art that anyone recognized the importance of increased ion-pairing to methylene enolate monoaddition. In addition, there remains a need to control the reaction of multi-functional Michael donors with multi-functional acceptors at stoichiometric ratios near 1:1 equivalents to minimize polydispersity and molecular weight together with maximization of final functionality.